Efficacy and safety of motesanib an oral inhibito

Authors: Robert S Benjamin Patrick Schöffski Jörg Thomas Hartmann Allan Van Oosterom Binh Nguyen Bui Justus Duyster Scott Schuetze JeanYves Blay Peter Reichardt Lee S Rosen Keith Skubitz Sheryl McCoy YuNien Sun Daniel E Stepan Laurence Baker

Publish Date: 2010/09/14

Volume: 68, Issue: 1, Pages: 69-77

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Abstract

This multicenter phase 2 study assessed the tolerability and efficacy of motesanib an oral inhibitor of Kit plateletderived growth factor receptor PDGFR and vascular endothelial growth factor receptors VEGFR in patients with imatinibresistant gastrointestinal stromal tumors GISTPatients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred The primary endpoint was confirmed objective tumor response per RECIST and independent review Secondary endpoints included progressionfree survival PFS time to progression TTP objective response by 18FDGPET and by changes in tumor size and/or density Choi criteria pharmacokinetics and safetyIn the patients evaluable for response N = 102 the objective response rate was 3 59 of patients achieved stable disease with 14 achieving durable stable disease ≥24 weeks 38 had disease progression Higher objective response rates were observed per 18FDGPET N = 91 30 and Choi criteria 41 The median PFS was 16 weeks 95 CI = 14–24 weeks the median TTP was 17 weeks 95 CI = 15–24 weeks The most common motesanib treatmentrelated grade 3 adverse events included hypertension 23 fatigue 9 and diarrhea 5 Motesanib did not accumulate with daily dosingUntil the success of imatinib mesylate patients with metastatic gastrointestinal stromal tumors GIST had a dismal prognosis since no systemic therapy provided clinical benefit Surgery is the initial therapy for patients with primary resectable GIST however approximately half of all patients eventually develop metastatic disease 1 Mutually exclusive gainoffunction mutations in the KIT protooncogene occurring in 85–90 of GISTs or in the plateletderived growth factor receptor α gene PDGFRA about 5 of tumors play a fundamental role in the development of GISTs 2 Imatinib a selective inhibitor of Kit and PDGFR kinase activity has been shown to substantially improve clinical outcomes in patients with advanced disease 3 4 However approximately 14 of treated patients exhibit primary imatinib resistance which is associated with shortened survival and many if not all develop secondary resistance after an initial response 3 4 Sunitinib malate a multikinase inhibitor has recently been demonstrated to be effective as secondline therapy in imatinibresistant GIST 5 The duration of secondary disease control with sunitinib is much shorter though than the initial control with imatinib despite considerable toxicity indicating that alternative therapies are needed 5Motesanib is a highly selective oral inhibitor of VEGF receptors VEGFR 1 2 and 3 and PDGFR IC50 84 nmol/L In addition motesanib potently inhibits wildtype Kit in vitro IC50 8 nmol/L 6 Motesanib has also been shown to inhibit autophosphorylation of a number of clinically relevant primary Kit mutants with greater potency than imatinib and has demonstrated activity against some imatinibresistant mutants eg Y823D and D816H 7 suggesting that it may have antitumor activity in imatinibresistant GIST In preclinical studies motesanib induced significant tumor regression in xenograft models of human breast carcinoma 8 nonsmall cell lung cancer 9 medullary thyroid cancer 10 and epidermoid and colon carcinoma 6 11 When tumor blood vessel density was investigated the results showed that motesanib treatment selectively targeted neovascularization indicating that the observed antitumor effect was mediated at least in part by inhibition of angiogenesis Motesanib did not inhibit the proliferation of tumor cells in vitro 6 8 9 10 In the phase 1 firstinhuman study in solid malignancies a motesanib dose of 125 mg once daily was established as the maximum tolerated dose In that study three patients with thyroid cancer and one patient with leiomyosarcoma achieved a partial response 12

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